JP7333269B2 - Rescue treatment for postoperative nausea and vomiting - Google Patents

Description

The present invention relates to the use of amisulpride in the treatment of postoperative nausea and/or vomiting (PONV).

PONV is a condition that occurs in approximately 30% of all surgical patients and 70% of high-risk patients. Risk factors for PONV include type of surgery, gender, smoking history, history of PONV or motion sickness, length of surgery, use of volatile anesthetics, and use of opioid analgesics. In general, women are more prone to PONV than men, as are non-smokers and those with a previous history of PONV or motion sickness.

PONV presents a significant problem for patients and healthcare providers. It is often rated above postoperative pain as the complication most feared by patients, and is therefore a major source of anxiety and patient distress. PONV may delay patient discharge from hospital, or may result in readmission after inpatient procedures, and may require outpatient admission. This has huge economic and social impacts. As the rate of resistant infections in hospitals increases, it may affect clinical outcomes.

A number of mechanisms have been implicated in PONV, the most prominent being the release of serotonin from the intestinal wall and activation of the chemoreceptor trigger zone in the brain. Therefore, several different receptors appear to be involved in PONV, and these represent effective targets for drug therapy. The most important are the serotonergic _5HT3 receptors and the dopaminergic _D2 and possibly _D3 receptors.

Despite routine use of prophylactic antiemetics in intermediate- and high-risk patients, PONV still affects approximately 30-40% of patients, even on the current standard of care with _5HT3 antagonists and corticosteroids. There remains a high need for additional agents that are occurring in cases, are effective and safe, especially those with different mechanisms of action.

The use of amisulpride as an antiemetic agent is described in WO2011/110854 published on 15 September 2011 claiming priority from UK patent specification GB1004020.2 filed on 11 March 2010, which includes: Both of which are hereby incorporated by reference in their entirety.

A multicenter, double-blind, randomized, dose-ranging phase II study (conducted by the applicant) evaluated amisulpride 1 mg, 5 mg, and A dose of 20 mg was administered intravenously and a fourth group received a placebo. The incidence of PONV was low in all amisulpride groups and was significantly lower at 1 mg (48%, p<0.05) and 5 mg (40%, p<0.01) compared to placebo (69%). This suggests that 5 mg is at or near the bottom of the U-shaped dose-response curve when assessing the incidence of PONV.

Applicants conducted two multicenter, double-blind, randomized, placebo-controlled phase III clinical trials involving 626 evaluable adult surgical patients at intermediate and high risk of PONV (prevention) , 5 mg of amisulpride was able to reduce the incidence of PONV to 48% compared to 59% with placebo (p<0.01).

In an applicant-conducted, multicenter, double-blind, randomized phase III trial involving 1147 evaluable adult surgical patients at high risk of PONV (prevention), amisulpride 5 mg versus standard antiemetics The combination was able to reduce the incidence of PONV to 42%, whereas the combination of placebo and standard antiemetics reduced it to 53% (p<0.001).

Another clinical trial conducted by applicant compared 5 mg and 10 mg doses of amisulpride to placebo for the treatment of PONV in patients who did not receive prior prophylaxis. There was no difference in clinical efficacy between the 5 mg and 10 mg doses, suggesting that both doses are in the plateau of U-shaped dose-response curves. Both doses were significantly better than placebo in treating PONV.

WO2011/110854

The present invention is based, at least in part, on the results of a study conducted by Applicant of amisulpride as a rescue treatment for PONV (ie, in patients who received prior prophylaxis for PONV but subsequently developed PONV). As expected, amisulpride was found to be effective as a salvage treatment for PONV (following an episode of vomiting and/or nausea); It was found to be more effective than the 5 mg dose of amisulpride as salvage therapy. This was completely unexpected, especially given the results of the clinical trials described above, which suggest that there should be no difference between the two doses.

According to a first aspect, amisulpride is useful for the treatment of post-operative nausea and/or vomiting in a patient, wherein the patient has already been administered post-operative nausea and/or vomiting prophylaxis, The dose of amisulpride is 7.5-15 mg.

According to a second aspect, there is provided a method of treating postoperative nausea and/or vomiting in a patient, comprising administering amisulpride to the patient, wherein the patient is administered a prophylactic agent for postoperative nausea and/or vomiting. and the dose of amisulpride is 7.5 to 15 mg.

Amisulpride has a single chiral center and exists in two enantiomers, (S-) amisulpride and (R+) amisulpride. It may be preferred to use the racemate, or (S-) amisulpride substantially free of the (R+) enantiomer. Nearly all therapeutic activity has been reported to be found in the (S-) enantiomer, so use of this enantiomer may reduce doses by 50% (e.g., 50%, 60%, 70%) compared to the racemate. %, 80%, or 90%, or 50% to 60%, 60% to 70%, 70% to 80%, or 80% to 90%).

A racemic mixture or racemate of amisulpride means that the amisulpride contains both the (S-) amisulpride and the (R+) enantiomer. For example, a racemic mixture may contain 40% to 60% (S-) amisulpride and 60% to 40% (R+) enantiomer. In some embodiments, the racemic mixture may contain about 50% (S-) amisulpride and about 50% (R+) enantiomer.

(S-) amisulpride that is substantially free of the (R+) enantiomer contains less than 10%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% of the (R+) enantiomer). For example, (S-) amisulpride that is substantially free of the (R+) enantiomer contains less than 2% or less than 1% of the (R+) enantiomer.

As used herein, the term post-operative nausea and/or vomiting (PONV) has its conventional meaning in the art. It is well understood in the art to mean the occurrence of one or more vomiting episodes (vomiting and/or nausea) or the occurrence of the desire to vomit (nausea) following a surgical procedure. Nausea involves the same physiological mechanisms as vomiting, but occurs against a closed glottis. PONV may be defined as nausea and/or vomiting occurring within 48 hours after completion of the surgical procedure. It may also be defined as nausea and/or vomiting occurring within 24 hours after the completion of the surgical procedure.

As used herein, "emetic episode" means an episode of vomiting and/or an episode of nausea.

As used herein, "episode of nausea" means an episode of nausea. This may be indicated by the patient reporting a desire to vomit or requesting an antiemetic.

As used herein, "surgical procedure" has its conventional meaning in the art. Preferably, it involves the administration of general anesthesia, eg general inhalation anesthesia. Treatment may be elective surgery (open or laparoscopic) under general anesthesia. It should preferably be scheduled to last at least 1 hour from induction of anesthesia to extubation. The wound is closed before extubation.

As used herein, the term "completion of the surgical procedure" has its conventional meaning in the art and is understood by those skilled in the art. Usually coincides with wound closure at the end of surgery.

As used herein, the term "about" or "substantially" when used in conjunction with a numerical value (e.g., 5, 10%, 1/3) is a numerical value that may be less than or greater than that number. indicate the range. For example, "about 5" refers to a numerical range 10%, 5%, 2%, or 1% less or greater than 5, such as 4.5 to 5.5, or 4.75 to 5.25, or 4.9 to 5.1, or Shows a range of 5.05. In some examples, "about 5" denotes a numerical range that is 2% or 1% less or greater than 5, such as 4.9 to 5.1, or 4.95 to 5.05.

In one aspect of the invention, the dose of amisulpride is 7.5 mg to 15 mg. Preferably, an effective amount (ie dose) of amisulpride comprises 8-15 mg amisulpride, more preferably 8.5, 9, or 9.5-15 mg. The dose of amisulpride may be 7.5 to 14.5, 14, 13.5, 13, 12.5, 12, 11.5, 11, or 10.5. Any of the aforementioned range limits may be combined with each other. Preferably, the dose is 8-12 mg, more preferably 9-12 mg, most preferably about 10 mg of amisulpride. A dose of 10 mg is most preferred. Preferably, amisulpride is in the form of a racemic mixture.

Preferably, amisulpride is administered as a single daily dose.

Preferably, amisulpride is administered as the racemate. When administered as the S-enantiomer, the dose may be altered (eg, halved) accordingly.

According to the present invention, amisulpride is used to "treat" PONV. This means that the patient is already PONV (as defined above). Also, according to the present invention, the patient has already been administered a prophylactic agent for PONV. Not surprisingly, therefore, prevention of PONV has not been successful.

"Prophylaxis" of PONV according to the present invention is administered prior to treatment of PONV. "Prophylactic agent" means a drug that is administered with the intention/purpose of preventing PONV. Suitable drugs will be known to those skilled in the art. Examples are provided below.

It may be advantageous to administer amisulpride in combination with other antiemetic agents (ie, other than amisulpride). "Other antiemetic agents" are preferably other classes of antiemetic agents that may add additional efficacy benefits. Therefore, preferably the different antiemetic agent is not a _D2 antagonist. These include, but are not limited to, steroids, most preferably dexamethasone; _5HT3 antagonists, including but not limited to ondansetron, granisetron, and palonosetron; and _NK1 antagonists, such as aprepitant, netupitant, or lorapitant. is included. Amisulpride may be combined with metoclopramide, which has both _D2 and _5HT3 properties. Preferably, the other antiemetic agent is ondansetron, granisetron, or dexamethasone. Amisulpride may be combined with one or more (eg, two or three) different antiemetic agents. Other classes of drugs may be administered via any suitable route of administration (eg, via routes of administration common to that drug, such as orally, intravenously, or intramuscularly). In some instances, other classes of drugs may be administered within 6 hours of completion of surgery. In other examples, other classes of drugs may be administered 6 hours after completion of surgery.

The prophylactic agent is preferably administered prior to completion of surgery. In a preferred embodiment, prophylaxis is given for a period of time from about 4 hours prior to the surgical procedure until the end of wound closure/surgical procedure. Preferably, it is administered by the end of wound closure/surgical procedure, more preferably prophylaxis is administered at the time of anesthesia (and more preferably at the time of anesthesia induction).

There are numerous prophylactic agents suitable for use in the present invention and these are well known to those skilled in the art. A particular prophylactic agent may be selected based on a number of factors, such as age and weight, or whether other particular medications are being taken, for example. Preferably, the prophylactic agent is an antiemetic that is not amisulpride. More preferably, the prophylactic agent is not a dopamine-2 ( _D2 ) antagonist.

In some embodiments, the prophylactic agent is an antiemetic agent selected from _5HT3 antagonists, corticosteroids, antihistamines ( _H1 ), anticholinergics, _H2 antagonists, or _NK1 antagonists. Prophylactic agents may be selected from any of the antiemetic agents described above (ie, combination therapy).

The _5HT3 antagonist can be ondansetron, granisetron, palonosetron, tropisetron, or dolasetron. Preferred are ondansetron, granisetron, or palonosetron. More preferred is ondansetron. The corticosteroid can be dexamethasone, hydrocortisone, betamethasone, methylprednisolone, or prednisolone. Preferred is dexamethasone. The antihistamine (H ₁ ) can be dimenhydrinate, hydroxyzine, diphenhydramine, promethazine, cyclizine, or meclizine. The anticholinergic agent can be scopolamine/hyoscine. The _H2 antagonist can be famotidine. _NK1 antagonists can be aprepitants. The _D2 antagonist, when used as a prophylactic antiemetic, can be haloperidol, droperidol, or domperidone.

General dosages for the various antiemetic agents listed above are known to those skilled in the art. For example, ondansetron is generally dosed between 2 and 20 mg, or between 2 and 15 mg, or about 10 mg, or about 4 mg. For granisetron, the dose is generally 1-3 mg, eg 1 mg. For dexamethasone, typical doses are 4-20 mg, eg 4 mg.

Amisulpride for use in accordance with the present invention can be packaged for sale with accompanying instructions for use. The instructions for use (drug label) should state that the patient to be treated should have undergone a surgical procedure and should be selected from a group of patients who have received prior prophylaxis for PONV and have not been successful (i.e. salvage therapy). ). It is also preferable to specify that the dose of amisulpride is 10 mg.

Amisulpride for use in the present invention is preferably formulated (and intended for intravenous administration) as an intravenous formulation. Amisulpride can be in the form of salts, hydrates, or solvates. Salts include pharmaceutically acceptable salts such as acid addition salts derived from inorganic or organic acids, such as hydrochloride, hydrobromide, p-toluenesulfonate, phosphate, sulfate, Perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates, and benzoates.

Salts may also be formed with bases. Such salts include salts derived from inorganic or organic bases, for example alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, morpholine salts, piperidine salts, dimethyl Amine salts and organic amine salts such as diethylamine salts are included.

Intravenous formulations of amisulpride for use in the present invention may be in the form of sterile injectable aqueous or non-aqueous (eg, oily) solutions or suspensions. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, phosphate buffered saline, Ringer's solution and isotonic saline. In addition, sterile, fixed oils may be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid may be used in the preparation of intravenous formulations of the invention. Suspensions may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, dispersing or wetting agents such as natural phosphatides such as lecithin, or Condensates of alkylene oxides with fatty acids, such as polyoxyethylene stearates, or of ethylene oxide with long-chain fatty alcohols, such as heptadecaethyleneoxycetanol, or of ethylene oxide with partial esters derived from fatty acids and hexitol. , for example, condensates of polyoxyethylene with partial esters derived from fatty acids and hexitol anhydride, such as polyoxyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin. It may contain an agent.

Injectable compositions are generally aqueous and contain buffers such as citrate buffer. Other ingredients may not be required. The pH of such compositions may be, for example, between 4 and 7, eg about 5.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are known.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or mixtures thereof. Suitable emulsifiers are natural gums such as gum acacia or gum tragacanth, natural phosphatides such as soybean, lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate and condensates of said partial esters with ethylene oxide, For example, it can be polyoxyethylene sorbitan monooleate.

An intravenous unit dose of amisulpride suitable for use in the present invention is preferably a single injection containing amisulpride. In a preferred embodiment, this may be in the form of a vial of active agent and a syringe and needle, or a pre-filled syringe/needle combination.

In some embodiments, amisulpride is included in a non-IV injectable formulation. It may be in the form of solid or liquid preparations and may be formulated for oral administration. Solid formulations may be in the form of tablets or capsules, melted tablets, or dispersible powders or granules, which may require addition to water. Liquid formulations may be in the form of an aqueous or oily suspension or in the form of syrups and packaged in vials.

Amisulpride may be in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ambient temperature but liquid at rectal temperature and thus melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

Transdermal and transmucosal patches, creams, ointments, jellies, solutions, or suspensions may be used for topical delivery. Sublingual delivery may use fast dissolving tablet formulations, as well as many of those described above. For oral administration, which is the preferred administration, amisulpride may be administered as a tablet, capsule, or liquid.

In a preferred embodiment, the oral unit dose of amisulpride is in the form of one or more tablets, or one or more capsules. A unit dose of amisulpride may be provided in a blister pack.

Amisulpride formulations may include any number of pharmaceutically acceptable excipients, such as sweetening agents and preservatives.

Formulations of amisulpride suitable for use in the present invention are described in WO2011/110854.

Where the use or method of the invention provides for the administration of more than one drug, the drugs may be administered simultaneously, sequentially or separately. The drugs need not be packaged together (although this is an embodiment of the invention). There is no need to administer the drugs at the same time. As used herein, "separate" administration means that the drugs are administered as part of the same overall dosing regimen (which may include many days), but preferably on the same day. means that it is administered to As used herein, "simultaneously" means that the drugs are taken together or formulated as a single composition. As used herein, "sequentially" means that the drugs are administered at about the same time, preferably within about 1 hour of each other.

Prophylactic agents should have been administered before vomiting occurred. Preferably, it is administered as a single prophylactic dose.

Preferably, amisulpride is administered by IV infusion (push), preferably over a period of about 20 seconds to 20 minutes. For example, if the patient feels pain during the injection, it may be preferable to increase the injection time. In some embodiments, amisulpride is administered over about 1-15, 1-10, 1-5, or 1 or 2 minutes. Amisulpride is preferably administered in a single dose.

Amisulpride should be administered as soon as practicable following the first episode of vomiting and/or the first episode of nausea (e.g., first request for antiemetic to treat nausea, or report of desire to vomit). be. Preferably, amisulpride is administered within 1 hour of the first episode of vomiting and/or within 1 hour of the first episode of nausea. More preferably, it is administered within 30 minutes of the first episode of vomiting and/or within 30 minutes of the first episode of nausea. Even more preferably, it is administered within 15 minutes of the first emetic episode and/or within 15 minutes of the first nausea episode.

In some embodiments, no further dose of amisulpride is administered within 24 hours after the initial dose. In some embodiments, after the initial dose according to the present invention, at least one further dose is administered within about 24 hours, preferably within about 12 hours of the first dose.

In preferred embodiments, the patient is human.

The following studies illustrate the invention.

Research 1

protocol

A randomized, double-blind, placebo-controlled trial of IV injectable amisulpride as a treatment for pre-existing postoperative nausea and vomiting in pre-prophylaxis patients was conducted. The primary objective of this study was to compare the efficacy of 5 mg and 10 mg amisulpride to placebo for the treatment of pre-existing PONV in patients who received prior PONV prophylaxis.

This study was conducted in adult patients (age 18 years and older) with an expected duration of inhalation anesthesia of at least 1 hour who received prior PONV prophylaxis and who experienced PONV within 24 hours after surgery.

A single 5 mg or 10 mg dose of amisulpride or matching placebo was administered by slow IV administration over approximately 2 minutes.

The primary efficacy variable was the dichotomous success or failure of initial PONV treatment, with success defined as no vomiting episode (vomiting or nausea) 30 minutes to 24 hours after administration of study drug and 24 hours after administration of study drug. was defined as no administration of antiemetic rescue medication at any time during the period (“complete remission”).

Secondary efficacy variables include:
- Incidence and severity of nausea (VRS score >0) and severe nausea (VRS score ≥4). Includes measures of nausea over time, such as the area under the nausea score curve for up to 24 hours.
- Occurrence of vomiting (including nausea) after administration of study drug.
• Use of antiemetic relief medications.
• Time to failure of initial PONV treatment.
• Sub-analysis of success and failure by various parameters, including time of onset and gender of PONV in relation to completion of surgery.

result

The complete remission (CR) rate was as follows.
Placebo (235 patients) 28.5%
Amisulpride 5 mg (237 patients) 33.8% (p=0.109)
Amisulpride 10 mg (230 patients) 41.7%, (p=0.003)

Conclusion

When used as a " rescue " therapy, i.e., to treat a patient with a PONV episode when prior prophylaxis was unsuccessful for the patient, administration of amisulpride at a dose of 10 mg (5 mg (compared to doses of In this situation, a dose of 10 mg amisulpride proved to be particularly effective. This can be a very effective reduction in length of stay in the post-anesthesia recovery room, which can benefit the healthcare provider.

Claims (8)

A medicament containing amisulpride for use in the treatment of postoperative nausea and/or vomiting (PONV) in a patient, said patient being administered postoperative nausea and/or vomiting (PONV) prophylaxis and undergoing a surgical procedure. , experienced postoperative nausea and/or vomiting (PONV) prior to administration of amisulpride , said prophylactic agent is not amisulpride, and the dose of amisulpride is 10 mg. 2. The medicament according to claim 1, wherein said prophylactic agent is not a dopamine-2 ( _D2 ) antagonist. 3. The prophylactic agent of claim 1 or 2, wherein the prophylactic agent is an antiemetic agent selected from _5HT3 antagonists, corticosteroids, antihistamines (H1), anticholinergics, _H2 antagonists, or _NK1 antagonists. Medicine. 4. The medicament according to any one of claims 1 to 3, wherein said amisulpride is administered separately, sequentially or simultaneously in combination with another antiemetic agent. 5. The medicament according to claim 4, wherein said other antiemetic agent is a _5HT3 antagonist, _NK1 antagonist or steroid. 6. The medicament according to claim 4 or claim 5, wherein said other antiemetic agent is dexamethasone, ondansetron, granisetron, palonosetron, aprepitant, netupitant, or lorapitant. 7. The medicament according to any one of claims 1 to 6, wherein said amisulpride is substantially in racemic form. 8. The pharmaceutical according to any one of claims 1 to 7, wherein said amisulpride is administered via an intravenous route.